The cytochrome P450 (CYP) system has been implicated in the metabolism of many drugs including dextromethorphan, codeine, hydrocodone, amphetamine, oxycodone and methamphetamine. These drugs have various pharmacological effects including analgesia, sedation and antussive effects (or the suppression of cough).
One of these, codeine, is an opioid drug that is widely used for pain relief (analgesia) and for cough suppression (anti-tussive). While most codeine use appears to be for medical purposes, there is increasing evidence that some individuals use this drug non-medically for its mood-altering properties (Jensen and Hansen, 1993; Isaac et al., 1995; Romach et al.).
The metabolism of codeine follows three major pathways: conjugation to codeine-6-glucuronide; N-demethylation to norcodeine; and O-demethylation to morphine. The conjugation pathway is quantitatively the most important, with codeine-6-glucuronide recovered in urine accounting for 70% of an oral dose of codeine. The corresponding values for N-demethylation and O-demethylation are approximately 7% and 5% respectively. About 4% is excreted unchanged (Yue et al., 1991). The O-demethylation pathway, although quantitatively small, is of pharmacological importance because morphine and some of its metabolites (morphine-6-glucuronide and normorphine) are pharmacologically more potent than codeine or any of its non-O-demethylated metabolites. The O-demethylation of codeine to morphine is catalyzed by the genetically polymorphic drug metabolizing enzyme cytochrome 2D6 (CYP2D6) (Dayer et al., 1988; Mortimer et al., 1990).
CYP2D6 is absent in approximately 7% of the Caucasian population due to the homozygous expression of inactivating mutations in the CYP2D6 gene (reviewed by Kroemer and Eichelbaum, 1995). Such individuals are referred to as `poor metabolisers` (PMs), while those who express functional CYP2 D6 enzymes are `extensive metabolisers` (EMs).
Previous studies have addressed the importance of metabolic O-demethylation to the analgesia, respiratory depression and decreased gastrointestinal motility of codeine (Sindrup et al., 1990; 1992; Desmeules et al., 1991; Caraco et al., 1996; Poulsen et al., 1996). Codeine analgesia was shown to be impaired in PMs as well as in EMs who had been temporarily converted to PMs through pretreatment with the potent and selective CYP2 D6 inhibitor quinidine (Sindrup et al., 1990, 1992). Diminished production of morphine in extensive metabolizers of codeine after quinidine was associated with significantly reduced respiratory, psychomoter and pupillary effects (Caraco et al., 1996). Increasing codeine's N-demethylation by rifampin treatment is associated with attenuation of codeine's respiratory and psychomoter effects in EMs but not CYP2 D6 deficient PMs (Caraco et al., 1997). The results of these studies therefore imply a substantial contribution by the O-demethylated metabolites to the pharmacologic properties of codeine. With respect to abuse and dependence potential however, the roles of parent drug and metabolites are largely unknown.
The pain-relieving properties of opioids are mediated by .mu. opioid receptors (Szekely, 1994). The O-demethylated metabolites of codeine have a substantially greater affinity for the .mu. receptor than do codeine or any of the non-O-demethylated metabolites, and this is the basis for their postulated importance in codeine analgesia (Sindrup and Brosen, 1995). For example, the affinity of morphine for the .mu. opiate receptors in 200-fold greater than that of codeine; the affinity of morphine-6-glucuronide, a metabolite of morphine, is 400-fold greater than that of codeine; and the affinity of normorphine, another morphine metabolite, is 50-fold greater than that of codeine (Chen et al., 1991). The subjective effects of opioid agonists considered important for abuse liability (such as subjective elation, euphoria, "liking", etc.) are also mediated through the .mu. receptors (Szekely, 1994; Di Chiara and North, 1992).
Another drug that is present in cough formulations is dextromethorphan (DEX). DEX is a methylated dextrorotatary analog of levorphanol (a morphine analog) (Bern and Peck, 1992), but it does not possess the full range of central nervous system effects common to opioid agonists (Tortella et al., 1989). The drug has been widely used for its antitussive properties for many years and is available as an over-the-counter preparation in most countries, including Canada and the United States. DEX has also been investigated as a possible pharmacotherapy for a variety of neurodegenerative disorders such as amyotrophic lateral sclerosis, (Hollander, 1994; Blin, 1996) idiopathic Parkinson disease, (Saenz, 1993; Montastruc, 1994) and Huntington disease (Walker, 1989). Experimental studies have investigated the analgesic properties of DEX in humans (Kauppila, 1995) and its use as possible pharmacotherapy for heroin addiction (Koyuncuoglu and Sadam, 1990). Dextromethorphan, or DEX, has been used in the USA for about 30 years and a large body of clinical experience has been used to formulate a safety profile for DEX. An anthology of adverse drug events has been analyzed, drawn both from published case records and a data base recording DEX-related adverse events spontaneously reported by physicians or pharmacists (Bern and Peck, Dextromethorphan. An overview of safety issues. Drug Safety. 7(3):190-9. 1992). The resulting safety profile indicates that adverse drug reactions are infrequent and usually not severe. The predominate symptoms are usually dose related and include neurological, cardiovascular and gastrointestinal disturbances. Particular safety concerns arise when monoamine oxidase inhibiting (MAOI) drugs and DEX are coadministered. In addition to adverse drug reactions, the safety profile of DEX is affected by episodic and sporadic abuse. In fact, abuse appeared to be the most significant hazard identified by analysis of spontaneous adverse event reporting. No evidence could be found that the well documented pharmacokinetic polymorphism observed with dextromethorphan is correlated with any clinically significant safety risk if it is used for short term treatment. In summary, the safety profile of dextromethorphan is reassuring, particularly relating to overdose in adults and children.
Dextrorphan (DOR) is a metabolite of dextromethorphan, being produced when DEX is metabolized by the liver enzyme cytochrome P4502D6 or CYP2 D6 (debrisoquine 4-hydroxylase). Conversion involves the removal of a methyl group (CII3) at position 6. This removal is termed "O-demethylation" and is the major route of removal of DEX from the body. Between 5 to 10% of the Caucasian population lack this enzyme, and in the remaining population the rate of metabolism (activity of this enzyme) can vary tremendously.
DOR is very similar chemically to DEX, but reacts with different receptors in the body, and shows a different affinity, or spectrum of affinities and subsequent actions for those receptors with which DEX also reacts. DOR is an active metabolite with anticonvulsant, sedative, and antitussive properties and an affinity for the phencyclidine (PCP) site of the ligand-gated channel of the N-methyl D-aspartate (NMDA) receptor complex (K.sub.1 =222 nM) (Wong, 1988). The affinity of DOR is similar to that of ketamine (D.sub.1 =200 nM) (Parsons, 1995) and is much higher than that of the parent drug, DEX; K.sub.1 =3500 nM (Newman, 1996). However, the binding affinity of DOR for the NMDA receptor complex is not as high as that of PCP (K.sub.1 =42 nM) (Wong et al., 1988), a prototypic NMDA antagonist (Hampton, 1982) and a well-known drug of abuse (Stillman, 1979). However, it is believed that DOR is principally responsible for the abuse potential of the parent drug dextromethorphan. Cough suppression can be mediated exclusively by the parent drug, DEX, and occurs in the absence of conversion to DOR, i.e., no metabolism is required for antitussive efficacy.
Hydrocodone is also used as an antitussive, analgesic and sedative medication and it too undergoes the same routes of metabolism as DEX and codeine: Hydrocodone is metabolised to hydromorphone, which has a higher abuse potential than the parent compound. As such, as for DEX and codeine, the metabolities appear to contribute to the abuse potential of the parent drug, however, the roles of parent drug and metabolite(s) are largely unknown.
In view of the abuse potential of drugs found in cough formulations (such as dextromethorphan, codeine and hydrocordone) there is a need for improved cold or cough formulation that have a reduced abuse potential but long lasting therapeutic effect.